Spiridon Papapetropoulos

A Genomic Pathway Approach to a Complex Disease: Axon Guidance and Parkinson Disease

While major inroads have been made in identifying the genetic causes of rare Mendelian disorders, little progress has been made in the discovery of common gene variations that predispose to complex diseases. The single gene variants that have been shown to associate reproducibly with complex diseases typically have small effect sizes or attributable risks. However, the joint actions of common gene variants within pathways may play a major role in predisposing to complex diseases (the paradigm of complex genetics). The goal of this study was to determine whether polymorphism in a candidate pathway (axon guidance) predisposed to a complex disease (Parkinson disease [PD]). We mined a whole-genome association dataset and identified single nucleotide polymorphisms (SNPs) that were within axon-guidance pathway genes. We then constructed models of axon-guidance pathway SNPs that predicted three outcomes: PD susceptibility (odds ratio = 90.8, p = 4.64 × 10−38), survival free of PD (hazards ratio = 19.0, p = 5.43 × 10−48), and PD age at onset (R 2 = 0.68, p = 1.68 × 10−51). By contrast, models constructed from thousands of random selections of genomic SNPs predicted the three PD outcomes poorly. Mining of a second whole-genome association dataset and mining of an expression profiling dataset also supported a role for many axon-guidance pathway genes in PD. These findings could have important implications regarding the pathogenesis of PD. This genomic pathway approach may also offer insights into other complex diseases such as Alzheimer disease, diabetes mellitus, nicotine and alcohol dependence, and several cancers.

Lrrk2 and lewy body disease

The Lrrk2 kinase domain G2019S substitution is the most common genetic basis of familial and sporadic parkinsonism. Patients harboring the G2019S substitution usually present with clinical Parkinsons disease.

Vitamin E for prophylaxis against chemotherapy-induced neuropathy: A randomized controlled trial

Background: The authors conducted a pilot, randomized, open label with blind assessment, controlled trial to determine whether vitamin E supplementation has a neuroprotective effect in chemotherapy-induced peripheral nerve damage. Methods: Thirty-one patients with cancer treated with six courses of cumulative cisplatin, paclitaxel, or their combination regimens were randomly assigned in two groups and followed by neurologic examination and electrophysiologic study. Patients assigned in Group I (n = 16) received oral vitamin E at a daily dose of 600 mg/day during chemotherapy and 3 months after its cessation were compared to patients of Group II (n = 15), who received no supplementation and served as controls. The severity of neurotoxicity was summarized by means of a modified peripheral neuropathy score. Results: The incidence of neurotoxicity differed between the two groups, occurring in 4/16 (25%) patients assigned in the vitamin E supplementation group and in 11/15 (73.3%) patients assigned in the control group (p = 0.019). Mean peripheral neuropathy scores were 3.4 ± 6.3 for patients of Group I and 11.5 ± 10.6 for patients of Group II (p = 0.026). The relative risk (RR) of developing neurotoxicity was significantly higher in case of control patients, RR = 0.34, 95% CI = 0.14 to 0.84. Conclusion: Vitamin E supplementation in cancer patients may have an important neuroprotective effect.

Psychotic symptoms in Parkinson's disease. From description to etiology.

Psychotic symptoms are common in Parkinson’s disease (PD) and occur in at least 20% of medication-treated patients. Benign visual hallucinations usually appear earlier, while malignant hallucinations, confusional states, delusions, paranoid beliefs, agitation, and delirium become more frequent with disease progression. Virtually all antiparkinsonian drugs may produce psychotic symptoms. Cognitive impairment, increased age, disease duration and severity, depression, and sleep disorders have been consistently identified as independent risk factors for their development. Although the precise pathoetiologic mechanisms remain unknown, we review evidence that links ventral dopaminergic pathway dysfunction (overactivity) together with the involvement of other neurotransmitter system imbalances as likely contributors. The clinical importance of the proposed mechanism is that successful management of psychotic symptoms in PD may rely on a multitarget approach to restore neurotransmitter imbalances rather than focusing exclusively on the dopaminergic dysfunction.

Factors associated with drug–induced visual hallucinations in Parkinson's disease

AimsVisual hallucinations are common in medicationtreated Parkinsons disease (PD) patients. Although their etiology is unknown several factors seem to be involved in their pathogenesis. The aim of this study was to identify possible risk factors and determine clinical characteristics associated with the development of visual hallucinations in PD.Methods166 consecutive patients fulfilling clinical criteria for PD were studied. During a semi–structured interview, demographic characteristics and clinical variables were recorded. Motor, cognitive and psychiatric status was also assessed. Patients with and without visual hallucinations were compared using non–parametric tests, and logistic regression was applied to significant data.ResultsDuring the month before evaluation 20.4% of our patients experienced visual hallucinations (11.4% benign, 9% malignant). Logistic regression analysis identified three factors independently associated with visual hallucinations: long duration of Parkinsons disease, dementia, and disease severity as measured by the UPDRS total score.ConclusionsOur findings indicate that apart from well established risk factors such as cognitive impairment and disease duration, disease severity is also important for the development of visual hallucinations in PD. Furthermore, the presence of bradykinesia and instability, the absence of tremor and the severity of rigidity and bradykinesia (limb and axial) may act as cofactors.

Is there a role for naturally occurring cyanobacterial toxins in neurodegeneration?: The beta-N-methylamino-l-alanine (BMAA) paradigm

The naturally occurring, non-essential amino acid beta-N-methylamino-L-alanine (BMAA) has been recently found in high concentrations in brain tissues of patients with tauopathies such as the Amyotrophic Lateral Sclerosis-Parkinsonism-Dementia Complex (ALS/PDC) in the South Pacific island of Guam and in a small number of Caucasian, North American patients with sporadic Alzheimers disease. BMAA is produced by cyanobacteria that are present in all conceivable aquatic and/or terrestrial ecosystems and may be accumulated in living tissues in free and protein-bound forms through the process of biomagnification. Although its role in human degenerative disease is highly debated, there is mounting evidence in support of the neurotoxic properties of BMAA that may be mediated via mechanisms involving among others the regulation of glutamate. Glutamate-related excitotoxicity is among the most prominent factors in the etiopathogenesis of human neurodegenerative diseases. Due to the wide geographical distribution of cyanobacteria and the possible implications of BMAA neurotoxic properties in public health more research towards this direction is warranted.

Beyond Parkinson disease: amyotrophic lateral sclerosis and the axon guidance pathway.

Background We recently described a genomic pathway approach to study complex diseases. We demonstrated that models constructed using single nucleotide polymorphisms (SNPs) within axon guidance pathway genes were highly predictive of Parkinson disease (PD) susceptibility, survival free of PD, and age at onset of PD within two independent whole-genome association datasets. We also demonstrated that several axon guidance pathway genes represented by SNPs within our final models were differentially expressed in PD. Methodology/Principal Findings Here we employed our genomic pathway approach to analyze data from a whole-genome association dataset of amyotrophic lateral sclerosis (ALS); and demonstrated that models constructed using SNPs within axon guidance pathway genes were highly predictive of ALS susceptibility (odds ratio = 1739.73, p = 2.92×10−60), survival free of ALS (hazards ratio = 149.80, p = 1.25×10−74), and age at onset of ALS (R2 = 0.86, p = 5.96×10−66). We also extended our analyses of a whole-genome association dataset of PD, which shared 320,202 genomic SNPs in common with the whole-genome association dataset of ALS. We compared for ALS and PD the genes represented by SNPs in the final models for susceptibility, survival free of disease, and age at onset of disease and noted that 52.2%, 37.8%, and 34.9% of the genes were shared respectively. Conclusions/Significance Our findings for the axon guidance pathway and ALS have prior biological plausibility, overlap partially with PD, and may provide important insight into the causes of these and related neurodegenerative disorders.

The effect of depression on motor function and disease severity of Parkinson's disease.

OBJECTIVES Approximately 40% of patients with Parkinsons disease (PD) experience symptoms of depression. Our aim was to evaluate the effect of depression on disease severity, motor function and other phenotypic characteristics of PD. PATIENTS AND METHODS We studied 32 PD patients with major depression (PD-D) according to the DSM-IV criteria and 32 PD patients with no depression (PD-C) matched for gender, age of onset and duration. RESULTS Major depression in PD patients was associated with increased disease severity, poorer motor function and worse performance in the activities of daily living as measured by UPDRS scores. Furthermore, there was an association of depression with the severity of bradykinesia and axial rigidity. CONCLUSIONS Depression in PD can have a profound negative impact on a patients sense of wellbeing and motor functioning. Therefore, PD patients should be routinely and carefully screened for the presence of depression and appropriate management should be considered. Larger studies on the subject are warranted.

Multiregional gene expression profiling identifies MRPS6 as a possible candidate gene for Parkinson's disease

Combining large-scale gene expression approaches and bioinformatics may provide insights into the molecular variability of biological processes underlying neurodegeneration. To identify novel candidate genes and mechanisms, we conducted a multiregional gene expression analysis in postmortem brain. Gene arrays were performed utilizing Affymetrix HG U133 Plus 2.0 gene chips. Brain specimens from 21 different brain regions were taken from Parkinsons disease (PD) (n = 22) and normal aged (n = 23) brain donors. The rationale for conducting a multiregional survey of gene expression changes was based on the assumption that if a gene is changed in more than one brain region, it may be a higher probability candidate gene compared to genes that are changed in a single region. Although no gene was significantly changed in all of the 21 brain regions surveyed, we identified 11 candidate genes whose pattern of expression was regulated in at least 18 out of 21 regions. The expression of a gene encoding the mitochondria ribosomal protein S6 (MRPS6) had the highest combined mean fold change and topped the list of regulated genes. The analysis revealed other genes related to apoptosis, cell signaling, and cell cycle that may be of importance to disease pathophysiology. High throughput gene expression is an emerging technology for molecular target discovery in neurological and psychiatric disorders. The top gene reported here is the nuclear encoded MRPS6, a building block of the human mitoribosome of the oxidative phosphorylation system (OXPHOS). Impairments in mitochondrial OXPHOS have been linked to the pathogenesis of PD.

MAPT H1 haplotype is a risk factor for essential tremor and multiple system atrophy

Mutations in the microtubule-associated protein tau gene ( MAPT ) cause frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17).1 In addition, the major common MAPT- containing H1 haplotype is associated with increased risk for 2 parkinsonian disorders: progressive supranuclear palsy (PSP) characterized by 4-repeat tau pathology and Parkinson disease (PD) with α-synuclein pathology.2,3 However, the role of MAPT variation in other disorders with similar pathology or disease phenotype is unclear. We investigated the frequency of the MAPT H1 haplotype in both essential tremor (ET) and multiple system atrophy (MSA). ET is the most common movement disorder, and prior evidence has indicated a common link between ET and PD from clinical, epidemiologic, and pathologic studies as well as some reports of brainstem Lewy bodies at autopsy in patients with ET.4 MSA is a neurodegenerative disorder with α-synuclein pathology with a mixed clinical presentation combining autonomic dysfunction, parkinsonism, and cerebellar or pyramidal symptoms. The initial clinical signs of MSA with prominent parkinsonism can make it difficult to differentially diagnose it from early PD. In addition, up to 30% of patients with MSA with prominent parkinsonism may have a transient response to levodopa therapy.5 ### Methods. Genotyping of the MAPT H1 discriminating SNP (rs1052553) and H1c subhaplotype SNP (rs242557) was performed on a Sequenom MassArray iPLEX platform (San Diego, CA) (primer sequences are available on request) and analyzed with Typer 4.0 software. The rate of genotype calls was ≥95% in each population. The series contained 356 patients with clinical ET, 61 patients with pathologically confirmed MSA, and 409 US control subjects; all samples are North American Caucasians. Numerical variables were summarized with the sample mean, SD, and range (table e-1 on the …